Lecture 5

Pancreas – Central Organ for Digestive Enzymes

• The pancreas supplies virtually all enzymes necessary to digest the four major macronutrient classes; humans would starve without it.

  • Proteases → cleave proteins into peptides & amino-acids.

  • Amylolytic enzymes → hydrolyze starch to sugars.

  • Lipases → split triglycerides into free fatty acids & monoglycerides

  • Nucleases → fragment nucleic acids to free nucleotides.

Enzyme Synthesis, Packaging & Release

• Acinar cells synthesize enzymes ➜ package them into membrane-bound vesicles (zymogen granules).

• Most proteins leave the cell as pro-enzymes (zymogens)—inactive precursors stored near the apical pole until the proper stimulus triggers exocytosis.

• Key protection against autodigestion:

  • Zymogens remain inactive until they reach the small intestine (SI).

  • Pancreas co-secretes multiple trypsin inhibitors that block any accidental early activation.

  • If premature activation still occurs, trypsin can autodegrade itself.

Activation Cascade in the Duodenum

• Duodenal brush-border enzyme enterokinase (a.k.a. enteropeptidase) is tethered to the luminal membrane.

  • Cleaves \text{trypsinogen} → active trypsin.

  • Trypsin then catalyzes the conversion of virtually every other zymogen released from the pancreas ("self-propagating" cascade).

Major Pancreatic Proteases

Amylolytic and Lipolytic Enzymes:

• Amylolytic enzymes:

  • Pancreatic amylase cleaves starches to sugars

    • End product of this digestion is disaccharides and trisaccharides, maltose, maltotriose and alpha-limit dextrins

• Lipolytic enzymes:

  • Lipase → hydrolyzes triglycerides into free fatty acids and monoglycerides

  • Phospholipase A2 → hydrolyzes phospholipids into free fatty acids and lysophospholipids

  • Cholesterolesterase →hydrolyzes cholesterol-esters into free fatty acids and cholesterol

  • Some enzymes are secreted as active enzymes while others are secreted as inactive forms

Regulation of Pancreatic Juice Secretion

Intestinal Hormones & Their Triggers

• S-cells in duodenal epithelium sense luminal acid.

  • Release secretin into blood → binds pancreatic duct cells → ↑ secretion of \text{HCO}_3^--rich fluid.

• I-cells sense luminal fatty-acids & peptides.

  • Release cholecystokinin (CCK) → acts on acinar cells → exocytosis of zymogen granules.

• Negative feedback: once luminal pH is neutralized or fats/proteins absorbed, secretin & CCK secretion falls.

Parasympathetic (Vagal) Input

• Sight/smell/taste of food → vagal efferents (cephalic phase) → mild enzyme release ("mouth-watering" equivalence for pancreas).

• Gastric distension (gastric phase) continues vagal stimulation.

Phasic Overview

1. Cephalic – brain anticipatory signals.

2. Gastric – stomach stretch.

3. Intestinal (dominant) – chemical signals (acid, nutrients) in SI.

Systemic Effects of Secretin & CCK

• Both hormones inhibit gastrin, slowing gastric emptying & acid output—prevents duodenal overload.

• CCK additionally: contracts gallbladder, relaxes sphincter of Oddi, integrating bile & enzyme delivery.

Clinical Correlation – Cystic Fibrosis (CF)

• A defective chloride channel is produced

  • Patients suffer from pancreatic insufficiency

    • Produce all of the digestive enzymes

    • HCO3- and water secretion is so minimal that these enzymes do not get flushed from the ducts and do not reach the intestines

      • The retained proteolytic enzymes, which break down proteins, can result in pancreatic autodigestion

      • The cystic ducts in the pancreas are fibrotic because of constant autodigestion and inflammation

      • Patients must receive supplements of digestive enzymes and antacids to allow for adequate nutrition

Liver & Biliary System Anatomy

• Gallbladder – storage & concentration of bile between meals.

• Duct hierarchy: intrahepatic ducts → right/left hepatic ducts → common hepatic duct + cystic duct → common bile duct → merges with main pancreatic duct at the sphincter of Oddi → duodenum.

Dual Blood Supply

• Hepatic artery: systemic, 25\% of total flow – \text{O}_2-rich, nutrient-poor.

• Hepatic portal vein: venous, 75\% flow – nutrient-rich, \text{O}_2-poor (from GI tract, spleen, pancreas).

• Mixing occurs in hepatic sinusoids, draining centrally to the central vein.

Hepatic Lobule Microanatomy

• Hexagonal unit with a portal triad at each corner: hepatic artery branch, portal vein branch, bile ductule.

• Hepatocytes form plates; their apical membranes create canalicular networks to collect bile.

• Blood flows outside hepatocytes toward the central vein; bile flows inside canaliculi toward bile ducts → counter-current arrangement facilitates exchange.

Functional Portfolio of the Liver

• Exocrine: continuous production of bile (~0.5\,\text{L} day) for fat digestion.

• Metabolic: glucose ↔ glycogen interconversion, AA deamination, lipid handling—matching post-prandial supply to fasting demand.

• Detoxification: biotransformation (phase I/II) of xenobiotics & endogenous waste.

• Synthetic: plasma proteins (coagulation factors, albumin, lipoproteins).

Composition of Bile & Its Digestive Role

• Six major components:

  1. Bile acids (from cholesterol; amphipathic emulsifiers).

  2. Cholesterol (excretory route for excess).

  3. Phospholipids (mainly lecithin).

  4. Salts & water – primarily \text{Na}^+,\;\text{K}^+,\;\text{HCO}_3^-.

  5. Bile pigments: bilirubin (heme catabolism) – gives feces brown color.

  6. Trace metals (copper, etc.).

Emulsification & Micelles

• Problem: pancreatic lipase is water-soluble, whereas dietary fat forms large, water-insoluble droplets.

• Solution: bile acids + phospholipids coat droplets, confer negative/steric repulsion → droplets disperse (↑ surface area).

• End-products (FFA, MG) + bile components assemble into mixed micelles:

  • Single-layered, polar heads outward; non-polar core.

  • Maintain a reservoir of lipolysis products while a tiny fraction remains free in solution.

  • Free FFA & MG diffuse into enterocytes; micelles continuously dissociate/reform to sustain gradient.

Summary Flow of Fat Processing

1. Emulsion droplet stabilized by bile salts → dramatic surface-area expansion.

2. Pancreatic lipase + colipase hydrolyze TG.

3. FFA & MG partition into micelles; minuscule free pool absorbed.

4. Micellar recycling supports ongoing uptake until luminal fat depleted ➜ stimulus for CCK wanes (negative feedback).

Bile Formation & Storage

• Hepatocytes: synthesize bile acids; excrete phospholipids, cholesterol, bilirubin into canaliculi.

• Duct cells: add \text{HCO}_3^--rich fluid (stimulated by secretin) → volume & alkalinity.

• Gallbladder: concentrates bile (removes \text{H}_2\text{O} & salts) during interdigestive periods; CCK command empties it when chyme reaches duodenum.

Integrative Highlights & Exam Tips

• Trypsin sits at the apex of the protease activation hierarchy—knowing its control points (enterokinase, inhibitors, self-cleavage) is vital for understanding both physiology & pathology (e.g., pancreatitis).

• Secretin vs. CCK: remember the lumenal cue–cell–target triads: acid-S-cell-duct \text{HCO}_3^- vs. fats/AAs-I-cell-acinar enzymes + gallbladder.

• CF demonstrates how a single ion channel defect compromises multiple organs; in the pancreas, the domino starts with decreased \text{Cl}^-/\text{HCO}_3^- exchange.

• Lobule architecture embodies the counter-current principle: opposite flows for blood vs. bile optimize both detoxification and bile concentration.

• In fat digestion, appreciate that micelles do not cross the epithelium; only free FFA/MG diffuse—an often-tested concept.